Aldehydes, asymmetric alkylation

Pritchett et al.119 found that Ti(OPr )4 did not react with the bis(sulfon-amide) ligand itself, so they postulated that a chiral ligand initially reacted with the diethylzinc and was subsequently transferred to the titanium in the next step. Based on this assumption, they presented an improved procedure for the asymmetric alkylation of aldehyde to overcome the poor solubility of the li-... 

TABLE 2-14. Asymmetric Alkylation of Aromatic and Aliphatic Aldehydes... 

Triethylaluminum can be economically prepared on an industrial scale from aluminum hydride and ethylene,124 so a successful alkylation using organo-aluminum compound will certainly open up a new area for active research. Asymmetric alkylation of aromatic aldehydes with triethylaluminum was carried out by Chan et al.125 In the presence of (R)- or (.S )-134 and Ti(OPr1)4, alkylation proceeded readily, yielding the alcohol with high ee (Scheme 2-52). 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

The recently reported asymmetric alkylation of aromatic aldehydes with diethylzinc provides a nice example of the potential use of fluorous catalysts in sophisticated processes (Figure 5).1271 Addition... 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted much interest for their various applications in different synthetic transformations.2 Such simple structures, directly related to far better known chiral oxazolidinones,11,12,57 have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations, but mainly in condensation of their /V-acyl derivatives with aldehydes. Chiral OZTs have shown interesting characteristics in anti-selective aldol reactions58 or combined asymmetric addition. 

Radical cyclization of polyfunctional 5-hexenyl halides mediated by Et2Zn and catalyzed by nickel or palladium salts has been demonstrated to produce stereoselectively polyfunctional 5-membered carbo- and heterocycles [56, 57]. Based on this strategy a formal synthesis of methylenolactocin (11) was achieved (Scheme 20). The acetal 130, readily being built up by asymmetric alkylation of aldehyde 127 followed by reaction with butyl vinyl ether and NBS, served as the key intermediate for the construction of the lactone ring. Nickel(II)-catalyzed carbometallation was initiated with diethylzinc to yield exclusively the frans-disubstituted lactol 132, which could be oxidized directly by air to 134. Final oxidation under more forcing conditions then yielded the lactone (-)-75 as a known intermediate in the synthesis of (-)-methylenolactocin (11) [47aj. 

The resolution required for the synthesis of 288 or 291 can be avoided by making them by asymmetric reduction or by asymmetric alkylation of an aldehyde . The amines 291 (R = Et or w-Bu) formed in this way are lithiated with diastereoselectivity similar to, or greater than, that achieved with 288. a-Ethyl and a-butylphosphines 294 incidentally may show even higher selectivity than the more widely used a-methylphosphine ligand PPEA 283. 

The formation of aldehyde enolates is complicated by the disposition of aldehydes to undergo aldol condensation. Therefore, there are very few examples of direct asymmetric alkylations of aldehydes. 

Asymmetric alkylation of aldehydes is possible via enamines or azaenolates of imine derivatives (see Section D. 1.1.1.4.). Alkylation is also possible via enol ethers or esters (see Section 1.1.1.3.1.2.), although the use of these methods for asymmetric synthesis has not yet been explored. 

Aldehyde-derived SAMP/RAMP-hydrazones are alkylated in good overall chemical yields and excellent enantiomeric purities (see Table 4). Asymmetric inductions of up to 86% ee, obtained from alkylation reactions in tetrahydrofuran, were optimized to >90% ee by using diethyl ether as solvent8. Phenyl-substituted aldehydes are alkylated to products of lower enantiomeric purity (23-31 % ee), probably due to partial racemization of the sensitive aldehydes6, 25. 

The asymmetric addition of organomagnesium and organolithium reagents to a,P-unsaturated carbonyl compounds and especially imines can be achieved in situations where rigid chelation controls the geometry of the transition state. Stereospecific alkyl addition occurs in the case of a chiral leucine-derived imine to provide overall asymmetric alkyl addition to an a,P-unsaturated aldehyde (Scheme 107).380 381... 

Asymmetric Alkylation of Aldehydes Catalyzed by Chiral Lewis Bases... 

Asymmetric Alkylation of Aldehydes using Polymer and Dendritic Catalysts... 

An amino alcohol was found to accelerate the addition reaction of diethlylzinc to aldehyde [8], and then chiral amino alcohols were proved to be efficient chiral catalysts for asymmetric alkylation by using dialkylzinc reagents [9], Oguni reported a remarkable asymmetric amplification in chiral amino alcohol-promoted alkylation (Scheme 9.4). In the presence of (-)-l-piperidino-3,3-dimethyl-2-butanol (5) of 11% ee, benzaldehyde is alkylated enantioselectively to give (/ )-l-phenylpropanol with 82% ee [10]. Asymmetric amplification was also observed by Noyori using partially resolved (2.S )-3-exo-(dimethylamino)isobomeol (6) [11]. 

Asymmetric alkylation andaldol condensations.2 The enolate (2) of 1 reacts with primary iodides to give essentially a single product (3), in which the alkyl group is syn to the cyclopentadieny ring. Aldol condensation with acetone leads to only one observable product (4). Only two isomeric products are obtained on aldol condensation with prochiral aldehydes and ketones as expected for a rranx-enolate, the i/ww-aldol predominates or is the exclusive product (5) as in the case of pivaldehyde. 

A Et2Zn-(5, S)-linked-BINOL (21) complex has been found suitable for chemos-elective enolate formation from a hydroxy ketone in the presence of isomerizable aliphatic iV-diphenylphosphinoylimines.103 The reaction proceeded smoothly and /9- alkyl-yS-amino-a-hydroxy ketones were obtained in good yield and high enantioselectivity (up to 99% ee). A titanium complex derived from 3-(3,5-diphenylphenyl)-BINOL (22) has exhibited an enhanced catalytic activity in the asymmetric alkylation of aldehydes, allowing the reduction of the catalyst amount to less than 1 mol% without deterioration in enantioselectivity.104... 

The asymmetric alkylation of aldehydes by dialkylzinc reagents is one of the most intensively studied catalytic reactions [60-62]. Following the initial discoveries of Oguni and colleagues, including the recognition that a single... 

We turned our efforts to a synthesis in which a chiral 5-carbon unit would be coupled to a 6-carbon structure bearing functionality permitting resolution. The 5-carbon fragment would contain the hydrocarbon asymmetric center (C-8 of VII) the other unit would provide C-2. Commercially available (S>)-2-methyl 1-butanol was determined to be >99% pure. However, the R-alcohol (acid, aldehyde, etc.) would have to be synthesized. Asymmetric alkylations of chiral a-metallated amides were performed, but the enantiomeric excesses were not sufficiently high. In particular we noted that alkylations involving a short chain bifunctional compound (e.g., 3-methoxy-propyl iodide) provided slightly lower ee s than did the parent alkyl iodide. 

Asymmetric alkylation of aldehydes. Aldimines derived from the S-( - )-amine and propionaldehyde undergo alkylation (LD A, 1 equiv. of MgBt2) in a stereoselective manner (equation 1). 

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